Reactive oxygen species modulate macrophage immunosuppressive phenotype through the up-regulation of PD-L1.
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Date
2019-03-05ICR Author
Author
Roux, C
Jafari, SM
Shinde, R
Duncan, G
Cescon, DW
Silvester, J
Chu, MF
Hodgson, K
Berger, T
Wakeham, A
Palomero, L
Garcia-Valero, M
Pujana, MA
Mak, TW
McGaha, TL
Cappello, P
Gorrini, C
Type
Journal Article
Metadata
Show full item recordAbstract
The combination of immune checkpoint blockade with chemotherapy is currently under investigation as a promising strategy for the treatment of triple negative breast cancer (TNBC). Tumor-associated macrophages (TAMs) are the most prominent component of the breast cancer microenvironment because they influence tumor progression and the response to therapies. Here we show that macrophages acquire an immunosuppressive phenotype and increase the expression of programmed death ligand-1 (PD-L1) when treated with reactive oxygen species (ROS) inducers such as the glutathione synthesis inhibitor, buthionine sulphoximine (BSO), and paclitaxel. Mechanistically, these agents cause accumulation of ROS that in turn activate NF-κB signaling to promote PD-L1 transcription and the release of immunosuppressive chemokines. Systemic in vivo administration of paclitaxel promotes PD-L1 accumulation on the surface of TAMS in a mouse model of TNBC, consistent with in vitro results. Combinatorial treatment with paclitaxel and an anti-mouse PD-L1 blocking antibody significantly improved the therapeutic efficacy of paclitaxel by reducing tumor burden and increasing the number of tumor-associated cytotoxic T cells. Our results provide a strong rationale for the use of anti-PD-L1 blockade in the treatment of TNBC patients. Furthermore, interrogation of chemotherapy-induced PD-L1 expression in TAMs is warranted to define appropriate patient selection in the use of PD-L1 blockade.
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Subject
Cell Line, Tumor
Macrophages
Animals
Humans
Mice
Breast Neoplasms
Reactive Oxygen Species
Paclitaxel
Buthionine Sulfoximine
Glutathione
RNA, Messenger
Chemokines
Immunosuppressive Agents
Drug Therapy
Up-Regulation
Phenotype
Female
Tumor Microenvironment
Triple Negative Breast Neoplasms
B7-H1 Antigen
Research team
Target Evaluation and Molecular Therapeutics
Language
eng
License start date
2019-03
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2019, 116 (10), pp. 4326 - 4335
Publisher
NATL ACAD SCIENCES